boxed-textGoldbach-Mansky R et al. (2006) Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition. N Engl J Med 355: 581–592

Synopsis

Background

Neonatal-onset multisystem inflammatory disease (NOMID) is a rare, hereditary, systemic autoinflammatory disease. A large percentage of patients diagnosed with NOMID have been found to have a mutation in the gene CIAS1 (cold-induced autoinflammatory syndrome 1), which encodes cryopyrin.

Objective

The objective of this study was to assess the effect of anakinra, an interleukin 1 (IL-1) receptor antagonist, on a range of disease manifestations in patients with NOMID.

Design and intervention

This was a single-center study including patients aged 4–32 years, with active disease, who had at least two of the following symptoms: urticarial rash; CNS involvement; or radiographically evident epiphyseal or patellar overgrowth. All patients had been unresponsive to treatment with NSAIDs, disease-modifying antirheumatic drugs, or corticosteroids. Any patients receiving etanercept had a washout period of 21 days. Patients were started on daily subcutaneous injections of 1 mg/kg, which were increased to 2 mg/kg if clinical and laboratory indications of disease persisted. Efficacy of treatment was measured after 1, 3, and 6 months of treatment and patients were instructed to keep a daily diary of symptoms. Treatment with anakinra was halted after 3 months, and resumed after patient relapse or after 7 days.

Outcome measures

The primary outcome measures of this study were changes in daily symptoms, changes in levels of C-reactive protein and serum amyloid A, and changes in erythrocyte sedimentation rate, from baseline to 3 months, and from 3 months of treatment until disease flare. Secondary outcome measures included the occurrence of adverse events and the change in inflammation (as measured by serologic tests and imaging).

Results

A total of 18 patients participated in this study. All patients showed a positive and quick response to treatment with anakinra. In all cases, rash disappeared after treatment. There was a marked improvement in the daily report of disease-related symptoms (P <0.001) and decreases in the level of serum amyloid A (from a median of 174 mg/l to 8 mg/l, P <0.001), the level of C-reactive protein (from a median of 5.29 mg/l to 0.34 mg/l, P <0.001), and the erythrocyte sedimentation rate (P <0.001). Improvements in inflammation (measured by MRI) were observed in cochlear and leptomeningeal lesions. Hearing improved in six patients after 6 months of treatment, and median daily headache scores decreased from 0.5 to 0.1 (P <0.001). There were no treatment-related adverse events, and the presence of a CIAS1 mutation was not found to be related to the efficacy of anakinra in treating NOMID.

Conclusion

The authors conclude that anakinra is effective at improving clinical and laboratory manifestations of NOMID, irrespective of the presence of a CIAS1 mutation.

Commentary

Pathogenic mechanisms of NOMID were a mystery for over 20 years after the initial description of this rare and severe childhood disorder. Scientific advances in the last 5 years, however, have revolutionized our understanding of this previously difficult-to-treat disease. The identification of the CIAS1 gene, which encodes the protein cryopyrin, and the description of CIAS1 mutations in patients with cryopyrinopathies (including NOMID, familial cold autoinflammatory syndrome, and Muckle–Wells syndrome) bred the concept that these diseases are primarily caused by abnormalities in IL-1β biology. This hypothesis was supported by data implicating cryopyrin as a key component of the inflammasome, an intracellular complex that senses certain 'danger' signals and causes the cleavage of pro-IL-1β into its active form.1

Several IL-1-targeted therapies were developed following the discovery that IL-1 is an important mediator in many common chronic inflammatory disorders, including rheumatoid arthritis (RA). The only approved agent is a recombinant IL-1 receptor antagonist (anakinra) that is only modestly effective in RA, possibly because of unfavorable pharmacokinetics and its relatively weak effect on the IL-1 receptor. Recent experience with other IL-1 inhibitors, such as caspase-1 inhibitors and IL-1 TRAP, parallels the experience with anakinra, and suggests that IL-1 might not have a primary role in the synovial inflammatory features of RA.2 By contrast, IL-1 inhibitors, even anakinra, are remarkably effective in truly IL-1-dependent diseases like systemic-onset juvenile idiopathic arthritis, adult-onset Still's disease, and the cryopyrinopathies.3

In this article, Goldbach-Mansky and colleagues report the first open-label, controlled trial of anakinra in NOMID patients to include withdrawal of therapy and subsequent reinitiation of therapy upon disease flare. Although a randomized, placebo-controlled study design is the gold standard, the format of this study was appropriate for such a rare, severe disease with an expected dramatic response. The initial clinical and laboratory responses to therapy and reinitiation of therapy were remarkable in all patients. Disease flare was severe enough in several cases that the withdrawal phase was discontinued midstudy after ethical review. In the future, the risks of stopping therapy will need to be balanced against the unknown risks of long-term IL-1 blockade beginning in childhood.

The implications of this study stretch beyond rare genetic disorders such as NOMID. The hearing improvement seen in a third of patients and decreased cochlear enhancement seen in most patients could have implications for the treatment of other hearing disorders in which inflammation plays a pathogenic role. Cryopyrin and the inflammasome have also been implicated in the pathogenesis of crystal-induced diseases like gout and calcium pyrophosphate disease.4 We are learning that not all inflammation is the same; understanding the pathogenic mechanisms and specific cytokines involved in inflammatory diseases is crucial to developing targeted therapies rather than reaching randomly into our anticytokine armamentarium. Developing such therapies will require methodical, translational approaches drawing from pathophysiology, as in this study and others,5 instead of empiric therapeutic trials. There still remains a role for IL-1-targeted therapies in rheumatologic and other inflammatory diseases, but matching the correct drug to the patient is the true challenge.